Many of the Category A, B and C priority pathogens and toxins lead to disease as a result of an excessive host response. Our group at the University of Virginia, in partnership with Adenosine Therapeutics LLC has created a multidisciplinary and collaborative team with expertise in infectious disease, biodefense, immunology, chemistry and pharmacology. Together, we have developed and tested synthetic adenosine receptor agonists as novel immunotherapies that attenuate inflammatory responses and protect a host from different infections that cause disease through immune-mediated injury. Studies suggest that adenosine is a naturally occurring autocoid that limits tissue damage associated with inflammation. The effects of adenosine are controlled by four receptors (A1, A2A, A2B, and A3), which are variably expressed depending on cell lineage and species. Activation of A2AAR on immune cells produces a series of responses that in general can be categorized as anti-inflammatory. Preliminary data suggest that A2AAR maintain a tone of immunological restraint that protects against disease caused by excessive inflammatory responses triggered by several different pathogens. Thus, the general hypothesis is that A2AAR agonists protect the host from the morbidity and mortality of immune-mediated injury triggered by a broad spectrum of Category A, B and C pathogens and toxins. The objective of this proposal is to develop A2AAR agonists as novel biodefense immunotherapies. The first product will be ready for clinical testing within 3 years and second-generation compounds that can be delivered more easily via mucosal (oral or inhaled) routes will be ready for clinical evaluation in 5 years. This will be achieved in the following Specific Aims: Aim 1. Discovery and development of lead A2AAR agonists. Aim 2 Evaluation of the efficacy of A2AAR agonists as an immunotherapy. Aim 3. Define the mechanisms that can be used as correlates of protection in humans. Aim 4. Translation of A2AAR agonist function from animal models to applications in humans. These studies extend preliminary data showing A2AAR agonists complement conventional treatments to augment protection against agents relevant to biodefense. The proposal describes a systematic approach to develop, synthesize and test A2AAR agonists in relevant animal models as well as human cells in vitro. This work will build on past basic research to support new applied research and advanced product development for use in future clinical trials. [unreadable] [unreadable] [unreadable]